MedKoo Biosciences, Inc.
Tel:   +1-919-636-5577    Fax:   +1-919-980-4831    Email:   sales@medkoo.com
Search
Login Register
Search
MedKoo Cat#: 202901 | Name: Evofosfamide
Featured New

Description:

WARNING: This product is for research use only, not for human or veterinary use.

Evofosfamide, also known as TH-302, is a hypoxia-activated prodrug consisting of a 2-nitroimidazole phosphoramidate conjugate with potential antineoplastic activity. The 2-nitroimidazole moiety of hypoxia-activated prodrug TH-302 acts as a hypoxic trigger, releasing the DNA-alkylating dibromo isophosphoramide mustard moiety within hypoxic regions of tumors. Normoxic tissues may be spared due to the hypoxia-specific activity of this agent, potentially reducing systemic toxicity. Check for active clinical trials or closed clinical trials using this agent. (NCI).

Chemical Structure

Evofosfamide
Evofosfamide
CAS#918633-87-1

Theoretical Analysis

MedKoo Cat#: 202901

Name: Evofosfamide

CAS#: 918633-87-1

Chemical Formula: C9H16Br2N5O4P

Exact Mass: 446.9307

Molecular Weight: 449.04

Elemental Analysis: C, 24.07; H, 3.59; Br, 35.59; N, 15.60; O, 14.25; P, 6.90

Price and Availability

Size Price Availability Quantity
10mg USD 150.00 Ready to ship
25mg USD 250.00 Ready to ship
50mg USD 450.00 Ready to ship
100mg USD 750.00 Ready to ship
200mg USD 1,250.00 Ready to ship
500mg USD 2,450.00 Ready to ship
Show More
Bulk Inquiry
Buy Now
Add to Cart
Related CAS #
No Data
Synonym
TH302; TH 302; TH-302. Evofosfamide
IUPAC/Chemical Name
Phosphorodiamidic acid, N,N'-bis(2-bromoethyl)-, (1-methyl-2-nitro-1H-imidazol-5-yl)methyl ester.
InChi Key
UGJWRPJDTDGERK-UHFFFAOYSA-N
InChi Code
InChI=1S/C9H16Br2N5O4P/c1-15-8(6-12-9(15)16(17)18)7-20-21(19,13-4-2-10)14-5-3-11/h6H,2-5,7H2,1H3,(H2,13,14,19)
SMILES Code
O=P(NCCBr)(NCCBr)OCC1=CN=C([N+]([O-])=O)N1C
Appearance
Solid powder
Purity
>98% (or refer to the Certificate of Analysis)
Shipping Condition
Shipped under ambient temperature as non-hazardous chemical. This product is stable enough for a few weeks during ordinary shipping and time spent in Customs.
Storage Condition
Dry, dark and at 0 - 4 C for short term (days to weeks) or -20 C for long term (months to years).
Solubility
Soluble in DMSO, not in water
Shelf Life
>2 years if stored properly
Drug Formulation
This drug may be formulated in DMSO
Stock Solution Storage
0 - 4 C for short term (days to weeks), or -20 C for long term (months).
HS Tariff Code
2934.99.9001
More Info
According to wikipedia.com, TH-302 is an experimental anticancer agent that is in clinical development at Threshold Pharmaceuticals, Inc. It is activated only at very low levels of oxygen (hypoxia). Such levels are common in human solid tumors, a phenomenon known as tumor hypoxia. TH-302 exploits the activation of a nitroazole prodrug by a process that involves a one electron reduction mediated by ubiquitous cellular reductases such as the NADPH cytochrome P450 to generate a radical anion prodrug (RP). In the presence of oxygen (normoxia) the radical anion prodrug reacts rapidly with oxygen to generate the original prodrug and superoxide (SO). Under the low oxygen conditions of the hypoxic zones in tumors, however, the radical anion prodrug undergoes further irreversible reductions to the hydroxylamine (HA) followed by elimination, releasing the active drug and an azole derivative (AZ).   TH-302 started a Phase 1 clinical trial in 2007 in various solid tumors. The Phase 1 trial is a multi-center, open-label, dose-escalation study in patients with solid tumor cancers. The primary objectives of the study are to determine the maximum tolerated dose (MTD) and dose-limiting toxicities of TH-302 in patients with advanced solid tumors and to establish the appropriate dose to be tested in Phase 2 clinical trials. The secondary objectives of the trial include establishing the pharmacokinetics and assessing the anti-tumor activity of TH-302, as measured by objective response rate and duration of response, and to characterize the safety profile. Tumors will be evaluated at baseline and every eight weeks using the Response Evaluation Criteria In Solid Tumors (RECIST) criteria.    
Biological target:
Evofosfamide (TH-302) is a hypoxia-activated prodrug with IC50 of 10 μM and 1000 μM in hypoxia (N2) and normoxia (21% O2), respectively.
In vitro activity:
Enhanced TH-302 cytotoxicity under hypoxia was observed across 32 human cancer cell lines. One-electron reductive enzyme dependence was confirmed using cells overexpressing human NADPH:cytochrome P450 oxidoreductase and radiolytic reduction established the single-electron stoichiometry of TH-302 fragmentation (activation). Examining downstream effects of TH-302 activity, it was observed that hypoxia-dependent induction of γH2AX phosphorylation, DNA cross-linking, and cell-cycle arrest. Chinese hamster ovary cell-based DNA repair mutant cell lines were used. Lines deficient in homology-dependent repair, but not lines deficient in base excision, nucleotide excision, or nonhomologous end-joining repair, exhibited marked sensitivity to TH-302 under hypoxia. Consistent with this finding, enhanced sensitivity to TH-302 was also observed in lines deficient in BRCA1, BRCA2, and FANCA. Finally, TH-302 activity in the three-dimensional tumor spheroid and multicellular layer models was characterized. TH-302 showed much enhanced potency in H460 spheroids compared with H460 monolayer cells under normoxia. Multicellular layers composed of mixtures of parental HCT116 cells and HCT116 cells engineered to express an oxygen-insensitive bacterial nitroreductase showed that TH-302 exhibits a significant bystander effect. Reference: Mol Cancer Ther. 2012 Mar;11(3):740-51. http://mct.aacrjournals.org/cgi/pmidlookup?view=long&pmid=22147748
In vivo activity:
Three human PDAC xenografts with known differential responses to TH-302 were imaged prior to, and at 24 h and 48 hours following a single dose of TH-302 or vehicle to determine if imaging changes presaged changes in tumor volumes. DW-MRI was performed at five b-values to generate apparent diffusion coefficient of water (ADC) maps. For DCE-MRI, a standard clinically available contrast reagent, Gd-DTPA, was used to determine blood flow into the tumor region of interest. TH-302 induced a dramatic decrease in the DCE transfer constant (Ktrans) within 48 hours after treatment in the sensitive tumors, Hs766t and Mia PaCa-2, whereas TH-302 had no effect on the perfusion behavior of resistant SU.86.86 tumors. Reference: PLoS One. 2016 May 26;11(5):e0155289. https://www.ncbi.nlm.nih.gov/pmc/articles/pmid/27227903/
Solvent mg/mL mM
Solubility
DMSO 90.0 200.43
Ethanol 90.0 200.43
Water 10.0 22.27
Note: There can be variations in solubility for the same chemical from different vendors or different batches from the same vendor. The following factors can affect the solubility of the same chemical: solvent used for crystallization, residual solvent content, polymorphism, salt versus free form, degree of hydration, solvent temperature. Please use the solubility data as a reference only. Warming and sonication will facilitate dissolving. Still have questions? Please contact our Technical Support scientists.

Preparing Stock Solutions

The following data is based on the product molecular weight 449.04 Batch specific molecular weights may vary from batch to batch due to the degree of hydration, which will affect the solvent volumes required to prepare stock solutions.

Recalculate based on batch purity %
Concentration / Solvent Volume / Mass 1 mg 5 mg 10 mg
1 mM 1.15 mL 5.76 mL 11.51 mL
5 mM 0.23 mL 1.15 mL 2.3 mL
10 mM 0.12 mL 0.58 mL 1.15 mL
50 mM 0.02 mL 0.12 mL 0.23 mL
Formulation protocol:
In vitro protocol:
1. Meng F, Evans JW, Bhupathi D, Banica M, Lan L, Lorente G, Duan JX, Cai X, Mowday AM, Guise CP, Maroz A, Anderson RF, Patterson AV, Stachelek GC, Glazer PM, Matteucci MD, Hart CP. Molecular and cellular pharmacology of the hypoxia-activated prodrug TH-302. Mol Cancer Ther. 2012 Mar;11(3):740-51. doi: 10.1158/1535-7163.MCT-11-0634. Epub 2011 Dec 6. PMID: 22147748.
In vivo protocol:
1. Zhang X, Wojtkowiak JW, Martinez GV, Cornnell HH, Hart CP, Baker AF, Gillies R. MR Imaging Biomarkers to Monitor Early Response to Hypoxia-Activated Prodrug TH-302 in Pancreatic Cancer Xenografts. PLoS One. 2016 May 26;11(5):e0155289. doi: 10.1371/journal.pone.0155289. PMID: 27227903; PMCID: PMC4882075.
1: Pourmorteza M, Rahman ZU, Young M. Evofosfamide, a new horizon in the treatment of pancreatic cancer. Anticancer Drugs. 2016 Sep;27(8):723-5. doi: 10.1097/CAD.0000000000000386. PMID: 27232101. 2: Grkovski M, Fanchon L, Pillarsetty NVK, Russell J, Humm JL. 18F-fluoromisonidazole predicts evofosfamide uptake in pancreatic tumor model. EJNMMI Res. 2018 Jun 18;8(1):53. doi: 10.1186/s13550-018-0409-1. PMID: 29916085; PMCID: PMC6005997. 3: Jamieson SM, Tsai P, Kondratyev MK, Budhani P, Liu A, Senzer NN, Chiorean EG, Jalal SI, Nemunaitis JJ, Kee D, Shome A, Wong WW, Li D, Poonawala-Lohani N, Kakadia PM, Knowlton NS, Lynch CR, Hong CR, Lee TW, Grénman RA, Caporiccio L, McKee TD, Zaidi M, Butt S, Macann AM, McIvor NP, Chaplin JM, Hicks KO, Bohlander SK, Wouters BG, Hart CP, Print CG, Wilson WR, Curran MA, Hunter FW. Evofosfamide for the treatment of human papillomavirus-negative head and neck squamous cell carcinoma. JCI Insight. 2018 Aug 23;3(16):e122204. doi: 10.1172/jci.insight.122204. Erratum in: JCI Insight. 2023 Feb 22;8(4): PMID: 30135316; PMCID: PMC6141174. 4: Kishimoto S, Brender JR, Chandramouli GVR, Saida Y, Yamamoto K, Mitchell JB, Krishna MC. Hypoxia-Activated Prodrug Evofosfamide Treatment in Pancreatic Ductal Adenocarcinoma Xenografts Alters the Tumor Redox Status to Potentiate Radiotherapy. Antioxid Redox Signal. 2021 Oct 10;35(11):904-915. doi: 10.1089/ars.2020.8131. Epub 2020 Sep 15. PMID: 32787454; PMCID: PMC8568781. 5: Otowa Y, Kishimoto S, Saida Y, Yamashita K, Yamamoto K, Chandramouli GVR, Devasahayam N, Mitchell JB, Krishna MC, Brender JR. Evofosfamide and Gemcitabine Act Synergistically in Pancreatic Cancer Xenografts by Dual Action on Tumor Vasculature and Inhibition of Homologous Recombination DNA Repair. Antioxid Redox Signal. 2023 Sep;39(7-9):432-444. doi: 10.1089/ars.2022.0118. Epub 2023 May 23. PMID: 37051681; PMCID: PMC10623073. 6: Kumar S, Sun JD, Zhang L, Mokhtari RB, Wu B, Meng F, Liu Q, Bhupathi D, Wang Y, Yeger H, Hart C, Baruchel S. Hypoxia-Targeting Drug Evofosfamide (TH-302) Enhances Sunitinib Activity in Neuroblastoma Xenograft Models. Transl Oncol. 2018 Aug;11(4):911-919. doi: 10.1016/j.tranon.2018.05.004. Epub 2018 May 31. PMID: 29803017; PMCID: PMC6041570. 7: Yoon J, Kang SY, Lee KH, Cheon GJ, Oh DY. Targeting Hypoxia Using Evofosfamide and Companion Hypoxia Imaging of FMISO-PET in Advanced Biliary Tract Cancer. Cancer Res Treat. 2021 Apr;53(2):471-479. doi: 10.4143/crt.2020.577. Epub 2020 Oct 22. PMID: 33091966; PMCID: PMC8053876. 8: Bailleul Q, Navarin P, Arcicasa M, Bal-Mahieu C, Carcaboso AM, Le Bourhis X, Furlan A, Meignan S, Leblond P. Evofosfamide Is Effective against Pediatric Aggressive Glioma Cell Lines in Hypoxic Conditions and Potentiates the Effect of Cytotoxic Chemotherapy and Ionizing Radiations. Cancers (Basel). 2021 Apr 9;13(8):1804. doi: 10.3390/cancers13081804. PMID: 33918823; PMCID: PMC8070185. 9: Jamieson SM, Tsai P, Kondratyev MK, Budhani P, Liu A, Senzer NN, Chiorean EG, Jalal SI, Nemunaitis JJ, Kee D, Shome A, Wong WW, Li D, Poonawala-Lohani N, Kakadia PM, Knowlton NS, Lynch CR, Hong CR, Lee TW, Grénman RA, Caporiccio L, McKee TD, Zaidi M, Butt S, Macann AM, McIvor NP, Chaplin JM, Hicks KO, Bohlander SK, Wouters BG, Hart CP, Print CG, Wilson WR, Curran MA, Hunter FW. Evofosfamide for the treatment of human papillomavirus-negative head and neck squamous cell carcinoma. JCI Insight. 2023 Feb 22;8(4):e169136. doi: 10.1172/jci.insight.169136. Erratum for: JCI Insight. 2018 Aug 23;3(16): PMID: 36810255; PMCID: PMC9990753. 10: Huang Y, Tian Y, Zhao Y, Xue C, Zhan J, Liu L, He X, Zhang L. Efficacy of the hypoxia-activated prodrug evofosfamide (TH-302) in nasopharyngeal carcinoma in vitro and in vivo. Cancer Commun (Lond). 2018 May 3;38(1):15. doi: 10.1186/s40880-018-0285-0. PMID: 29764490; PMCID: PMC5993153. 11: Nytko KJ, Grgic I, Bender S, Ott J, Guckenberger M, Riesterer O, Pruschy M. The hypoxia-activated prodrug evofosfamide in combination with multiple regimens of radiotherapy. Oncotarget. 2017 Apr 4;8(14):23702-23712. doi: 10.18632/oncotarget.15784. PMID: 28423594; PMCID: PMC5410338. 12: Grande E, Rodriguez-Antona C, López C, Alonso-Gordoa T, Benavent M, Capdevila J, Teulé A, Custodio A, Sevilla I, Hernando J, Gajate P, Molina- Cerrillo J, Díez JJ, Santos M, Lanillos J, García-Carbonero R. Sunitinib and Evofosfamide (TH-302) in Systemic Treatment-Naïve Patients with Grade 1/2 Metastatic Pancreatic Neuroendocrine Tumors: The GETNE-1408 Trial. Oncologist. 2021 Nov;26(11):941-949. doi: 10.1002/onco.13885. Epub 2021 Jul 14. PMID: 34190375; PMCID: PMC8571752. 13: Laubach JP, Liu CJ, Raje NS, Yee AJ, Armand P, Schlossman RL, Rosenblatt J, Hedlund J, Martin M, Reynolds C, Shain KH, Zackon I, Stampleman L, Henrick P, Rivotto B, Hornburg KTV, Dumke HJ, Chuma S, Savell A, Handisides DR, Kroll S, Anderson KC, Richardson PG, Ghobrial IM. A Phase I/II Study of Evofosfamide, A Hypoxia-activated Prodrug with or without Bortezomib in Subjects with Relapsed/Refractory Multiple Myeloma. Clin Cancer Res. 2019 Jan 15;25(2):478-486. doi: 10.1158/1078-0432.CCR-18-1325. Epub 2018 Oct 2. PMID: 30279233; PMCID: PMC6335171. 14: Harms JK, Lee TW, Wang T, Lai A, Kee D, Chaplin JM, McIvor NP, Hunter FW, Macann AMJ, Wilson WR, Jamieson SMF. Impact of Tumour Hypoxia on Evofosfamide Sensitivity in Head and Neck Squamous Cell Carcinoma Patient-Derived Xenograft Models. Cells. 2019 Jul 13;8(7):717. doi: 10.3390/cells8070717. PMID: 31337055; PMCID: PMC6678517. 15: Sun JD, Liu Q, Ahluwalia D, Ferraro DJ, Wang Y, Jung D, Matteucci MD, Hart CP. Comparison of hypoxia-activated prodrug evofosfamide (TH-302) and ifosfamide in preclinical non-small cell lung cancer models. Cancer Biol Ther. 2016 Apr 2;17(4):371-80. doi: 10.1080/15384047.2016.1139268. Epub 2016 Jan 28. PMID: 26818215; PMCID: PMC5036787. 16: Spiegelberg L, van Hoof SJ, Biemans R, Lieuwes NG, Marcus D, Niemans R, Theys J, Yaromina A, Lambin P, Verhaegen F, Dubois LJ. Evofosfamide sensitizes esophageal carcinomas to radiation without increasing normal tissue toxicity. Radiother Oncol. 2019 Dec;141:247-255. doi: 10.1016/j.radonc.2019.06.034. Epub 2019 Aug 17. PMID: 31431383; PMCID: PMC6913516. 17: Anderson RF, Li D, Hunter FW. Antagonism in effectiveness of evofosfamide and doxorubicin through intermolecular electron transfer. Free Radic Biol Med. 2017 Dec;113:564-570. doi: 10.1016/j.freeradbiomed.2017.10.385. Epub 2017 Oct 28. PMID: 29111232. 18: Badar T, Handisides DR, Benito JM, Richie MA, Borthakur G, Jabbour E, Harutyunyan K, Konoplev S, Faderl S, Kroll S, Andreeff M, Pearce T, Kantarjian HM, Cortes JE, Thomas DA, Konopleva M. Phase I study of evofosfamide, an investigational hypoxia-activated prodrug, in patients with advanced leukemia. Am J Hematol. 2016 Aug;91(8):800-5. doi: 10.1002/ajh.24415. Epub 2016 Jun 25. PMID: 27169385; PMCID: PMC4946992. 19: Hunter FW, Devaux JBL, Meng F, Hong CR, Khan A, Tsai P, Ketela TW, Sharma I, Kakadia PM, Marastoni S, Shalev Z, Hickey AJR, Print CG, Bohlander SK, Hart CP, Wouters BG, Wilson WR. Functional CRISPR and shRNA Screens Identify Involvement of Mitochondrial Electron Transport in the Activation of Evofosfamide. Mol Pharmacol. 2019 Jun;95(6):638-651. doi: 10.1124/mol.118.115196. Epub 2019 Apr 12. PMID: 30979813. 20: Guo H, Ci X, Ahmed M, Hua JT, Soares F, Lin D, Puca L, Vosoughi A, Xue H, Li E, Su P, Chen S, Nguyen T, Liang Y, Zhang Y, Xu X, Xu J, Sheahan AV, Ba-Alawi W, Zhang S, Mahamud O, Vellanki RN, Gleave M, Bristow RG, Haibe-Kains B, Poirier JT, Rudin CM, Tsao MS, Wouters BG, Fazli L, Feng FY, Ellis L, van der Kwast T, Berlin A, Koritzinsky M, Boutros PC, Zoubeidi A, Beltran H, Wang Y, He HH. ONECUT2 is a driver of neuroendocrine prostate cancer. Nat Commun. 2019 Jan 17;10(1):278. doi: 10.1038/s41467-018-08133-6. PMID: 30655535; PMCID: PMC6336817.